Previous work in this laboratory indicates that chronic food restriction enhances central sensitivity to the rewarding, motor- and cellular-activating effects of diverse drugs of abuse and direct dopamine receptor agonists. Moreover, the behavioral augmenting effect of food restriction is reversed by 7-12 days of restored ad libitum feeding and recovery of body weight. In Study I of this application, the sustained subnormal levels of insulin and leptin that characterize the food-restricted rat are investigated as possible triggers by determining whether continuous intracerebroventricular infusion of "replacement" hormone reverses the augmenting effect of food restriction on drug reward and motor activation. Studies II-V investigate whether chronic food restriction alters immediate early gene expression and/or signal transduction mediated by multiple dopamine receptor types in limbic forebrain structures that regulate drug reward. Specifically, Study II examines c-fos expression induced by individual and combined administration of dopamine receptor type-selective agonists. Study III examines functional coupling between D-2 dopamine receptors and G-protein by measuring quinpirole-stimulated [35S]GTPgS binding. Study IV examines D-1 dopamine agonist-induced stimulation of adenylyl cyclase. Study V examines d-amphetamine-induced activation of extracellular signal-regulated kinase (ERK). Finally, Study VI seeks to establish whether the neuroadaptations identified in Studies II-V are reversed by the same regimens of restored ad libitum feeding or subchronic i.c.v, hormone administration that reverse the behavioral effects of food restriction. By clarifying the relationship between endocrine adiposity hormones, central neurotransmission, and sensitivity of brain reward circuitry, this work may improve our understanding of organismic variables that affect vulnerability to drug abuse and help explain the high comorbidity of drug abuse and eating disorders.